Bridging the species divide: The limits of rat models in capturing human PVOD mechanisms
Frédéric Perros, Cédric Chaveroux, David Montani
https://doi.org/10.1002/pul2.70016
Abstract
To the Editor,
We read with great interest the recent paper by Prabhakar et al., “Mechanisms underlying age-associated exacerbation of pulmonary veno-occlusive disease,”1 which investigates the role of the integrated stress response (ISR) in pulmonary veno-occlusive disease (PVOD). Their findings, focusing on the inhibition of the ISR and protein kinase R (PKR) in an experimental rat model, provide compelling evidence for potential therapeutic strategies to mitigate pulmonary vascular remodeling in PVOD, in both young and aged rats. The study is a significant step forward in understanding disease mechanisms, and the authors have executed an impressive investigation into the ISR's role. However, in light of our study,2 which explores human PVOD, we wish to highlight several critical distinctions between rat models and human disease. Specifically, we aim to address the differential roles of PKR and activating transcription factor 4 (ATF4) activation, the bone morphogenetic protein receptor type 2 (BMPR2)–SMAD-mothers against decapentaplegic (SMAD) axis, and the broader implications of these differences for translational research.